The present invention relates to chemical processes. More particularly, the present invention is concerned with an improved process for preparing dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione.
Dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione possesses useful pharmacological properties for enhancing memory and reversing the effects of amnesia caused by electroconvulsive shock. (See U.S. Pat. No. 4,372,966.)
The prior art discloses several alternative routes to dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione starting with one or another derivative of heptanedioic acid, generally a 4-substituted-heptanedioic acid such as the 4-nitro, 4-amino-, 4-oxo-, or 4-hydroxyimino-derivative. However, most of these processes involve numerous steps or produce low overall yields of the desired end-product, typically on the order of 50% or less. Consequently, there is a need for an improved method of preparing this pharmacologically useful agent.
U.S. Pat. No. 4,372,966 to Butler discloses a method whereby dimethyl 4-nitro-heptanedioate is catalytically reduced by the action of hydrogen in the presence of palladium to produce a mixture of methyl 5-oxo-2-pyrrolidinepropanoate and the corresponding free acid. The mixture is next treated with base and then acidified to convert the ester in the mixture to the free acid. In a final step, the 5-oxo-2-pyrrolidinepropanoic is converted by the action of acetic anhydride to dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione. The reported overall yield for this synthetic sequence is about 48%.
Lukes et al., Coll. Czech. Chem. Comm., 12: 278-279 (1947) disclose a method by which diethyl 4-(hydroxyimino)heptanedioate is catalytically reduced by the action of platiunum oxide in the presence of ferrous chloride to produce a mixture of ethyl 5-oxo-2-pyrrolidinepropanoate and 4-oxo-heptanedioic acid. The yield of the pyrrolidine derivative is reported as 40%.
Leonard et al., J. Am. Chem. Soc., 69: 690-692 (1947) disclose a method of preparing dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione comprising catalytically reducing dimethyl 4-nitro-heptanedioate by the action of hydrogen in the presence of platinum oxide to methyl 5-oxo-2-pyrrolidinepropanoate in 55% yield. This material is subsequently cyclized in 60% yield to dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione by heating for 30 hours under hydrogen at 250-300 atmospheres (2.5.times.10.sup.4- 3.0.times.10.sup.4 kPascal) in the presence of copper chromite.
Micheel et al., Ann. Chem., 581: 225-237 (1953) disclose the preparation of dihydro-1H-pyrrolizine3,5(2H,6H)-dione by first converting 4-aminoheptanedioic acid to the "half lactam" (i.e. 5-oxo-2-pyrrolidinepropanoic acid) and then cyclizing this material to the dione by the action of acetic anhydride.
Micheel et al., Chem. Ber., 88: 509-510 (1955) dislcose a method of preparing dihydro-1H-pyrrolizine-3,5(2H,6H)-dione in 56% yield by the reduction of 4-oxo-heptanedioic acid, followed by the treatment of the 5-oxo-2-pyrrolidinepropanoic acid thus formed with acetyl chloride in acetic acid.